Regulatory T cells promote cancer immune-escape through integrin αvβ8-mediated TGF-β activation

Alexandra Lainé, Ossama Labiad, Hector Hernandez-Vargas, Sébastien This, Amélien Sanlaville, Sophie Léon, Stéphane Dalle, Dean Sheppard, Mark A. Travis, Helena Paidassi and Julien C. Marie ()
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Alexandra Lainé: Tumor Escape Resistance and Immunity department, Cancer Research Center of Lyon INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Claude Bernard Université Lyon 1
Ossama Labiad: Tumor Escape Resistance and Immunity department, Cancer Research Center of Lyon INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Claude Bernard Université Lyon 1
Hector Hernandez-Vargas: Tumor Escape Resistance and Immunity department, Cancer Research Center of Lyon INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Claude Bernard Université Lyon 1
Sébastien This: CIRI, Centre International de Recherche en Infectiologie, Université de Lyon, INSERM U1111, Université Claude Bernard Lyon 1, CNRS UMR5308, ENS de Lyon
Amélien Sanlaville: Tumor Escape Resistance and Immunity department, Cancer Research Center of Lyon INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Claude Bernard Université Lyon 1
Sophie Léon: Plateforme Ex-Vivo, Département de Recherche Translationnelle et d’Innovation, Centre Léon Bérard
Stéphane Dalle: Tumor Escape Resistance and Immunity department, Cancer Research Center of Lyon INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Claude Bernard Université Lyon 1
Dean Sheppard: University of California San Francisco
Mark A. Travis: Lydia Becker Institute of Immunology and Inflammation, University of Manchester
Helena Paidassi: CIRI, Centre International de Recherche en Infectiologie, Université de Lyon, INSERM U1111, Université Claude Bernard Lyon 1, CNRS UMR5308, ENS de Lyon
Julien C. Marie: Tumor Escape Resistance and Immunity department, Cancer Research Center of Lyon INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Claude Bernard Université Lyon 1

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Presence of TGFβ in the tumor microenvironment is one of the most relevant cancer immune-escape mechanisms. TGFβ is secreted in an inactive form, and its activation within the tumor may depend on different cell types and mechanisms than its production. Here we show in mouse melanoma and breast cancer models that regulatory T (Treg) cells expressing the β8 chain of αvβ8 integrin (Itgβ8) are the main cell type in the tumors that activates TGFβ, produced by the cancer cells and stored in the tumor micro-environment. Itgβ8 ablation in Treg cells impairs TGFβ signalling in intra-tumoral T lymphocytes but not in the tumor draining lymph nodes. Successively, the effector function of tumor infiltrating CD8+ T lymphocytes strengthens, leading to efficient control of tumor growth. In cancer patients, anti-Itgβ8 antibody treatment elicits similar improved cytotoxic T cell activation. Thus, this study reveals that Treg cells work in concert with cancer cells to produce bioactive-TGFβ and to create an immunosuppressive micro-environment.

Date: 2021
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DOI: 10.1038/s41467-021-26352-2

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